title: Rasip1 mediates Rap1 regulation of Rho in endothelial barrier function through ArhGAP29.
abstract: Rap1 is a small GTPase regulating cell-cell adhesion, cell-matrix adhesion, and actin rearrangements, all processes dynamically coordinated during cell spreading and endothelial barrier function. Here, we identify the adaptor protein ras-interacting protein 1 (Rasip1) as a Rap1-effector involved in cell spreading and endothelial barrier function. Using Förster resonance energy transfer, we show that Rasip1 interacts with active Rap1 in a cellular context. Rasip1 mediates Rap1-induced cell spreading through its interaction partner Rho GTPase-activating protein 29 (ArhGAP29), a GTPase activating protein for Rho proteins. Accordingly, the Rap1-Rasip1 complex induces cell spreading by inhibiting Rho signaling. The Rasip1-ArhGAP29 pathway also functions in Rap1-mediated regulation of endothelial junctions, which controls endothelial barrier function. In this process, Rasip1 cooperates with its close relative ras-association and dilute domain-containing protein (Radil) to inhibit Rho-mediated stress fiber formation and induces junctional tightening. These results reveal an effector pathway for Rap1 in the modulation of Rho signaling and actin dynamics, through which Rap1 modulates endothelial barrier function.
authors.affiliation: Molecular Cancer Research, University Medical Center Utrecht, 3582 CG Utrecht, The Netherlands.
authors.forename: Anneke
authors.initials: A
authors.lastname: Post
authors.forename: Willem-Jan
authors.initials: WJ
authors.lastname: Pannekoek
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Ross
authors.forename: Ingrid
authors.initials: I
authors.lastname: Verlaan
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Brouwer
authors.forename: Johannes L
authors.initials: JL
authors.lastname: Bos
mesh_terms: D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology*; D020690:GTPase-Activating Proteins / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D011485:Protein Binding; D015398:Signal Transduction; D020827:rap1 GTP-Binding Proteins / Q000502:physiology*
chemical_list: C500429:ARHGAP29 protein, human; D020690:GTPase-Activating Proteins; D047908:Intracellular Signaling Peptides and Proteins; C487329:RASIP1 protein, human; D020827:rap1 GTP-Binding Proteins